Cognitive Impairment in Patients with
Chronic Pain: The Significance of Stress
Robert P. Hart, PhD, James B. Wade, PhD, and Michael F. Martelli, PhD
Address
Department of Psychiatry, VCU Health System, P.O. Box 980268,
Richmond, VA 23298-0268, USA.
Current Pain and Headache Reports 2003, 7:116126
Current Science Inc. ISSN 15313433
Copyright 2003 by Current Science Inc.
This review article examines the role of emotional distress
and other aspects of suffering in the cognitive impairment
that often is apparent in patients with chronic pain.
Research suggests that pain-related negative emotions and
stress potentially impact cognitive functioning independent
of the effects of pain intensity. The anterior cingulate cor-
tex is likely an integral component of the neural system
that mediates the impact of pain-related distress on cogni-
tive functions, such as the allocation of attentional
resources. A maladaptive physiologic stress response is
another plausible cause of cognitive impairment in patients
with chronic pain, but a direct role for dysregulation of the
hypothalamic-pituitary-adrenocortical axis has not been
systematically investigated.
Introduction
This article discusses studies that examine cognitive func-
tioning in patients with chronic pain with an emphasis on
the role of emotional distress and the mechanisms of
stress-related effects. The prevalence of chronic pain (ie,
persisting for at least 6 months) in the general US popula-
tion has been estimated to be in the range of 35 to 75 mil-
lion [1]. Cognitive dysfunction is one component of the
behavioral change that can occur in this common clinical
condition. Chronic pain and associated symptoms compli-
cate the presentation of other patients, including those
with documented or presumptive brain injury. Although
clarifying the impact of momentary pain is important, the
concomitants of chronic pain, such as mood change, sleep
disturbance, fatigue, and other aspects of suffering (eg, life-
style interference secondary to disability), seem to be more
closely related to cognitive impairment.
Sensory-discriminative and affective-motivational
components of pain appear to be processed in parallel by
different parts of the nociceptive system [2,3,4]. Medial
thalamic nuclei, the anterior and mid-cingulate, and
related structures appear to mediate the affective-
motivational component of pain. Some of the brain
structures involved in processing affective-motivational
dimensions of pain presumably are components of the
neural system mediating the impact of pain-related stress
on cognitive functioning.
Previous reviews have concluded that chronic pain is
commonly associated with neuropsychologic impairment
[5,6]. Impairments are most evident on tests assessing
attentional capacity, processing/psychomotor speed, and
memory. Although many of the previously reviewed stud-
ies assessed emotional status or used symptom inventories
that included items pertaining to characteristics such as
fatigue, mood state, and distress, few studies have systemat-
ically explored the relationship between these variables
and neuropsychologic test performance. The next section
summarizes studies that have not been previously reviewed
by Hart et al. [5]. A later section focuses on previously
reviewed and more recent studies that specifically address
the role of psychologic distress and mood disturbance on
cognition in patients with chronic pain.
Recent Neuropsychologic
Findings in Chronic Pain Populations
A study of more than 100 patients with head, neck, or back
pain who experienced decreased mental and physical func-
tioning [7] underscores the importance of clarifying
whether a patient with chronic pain is seeking financial
compensation. Twenty-nine percent of those seeking
financial compensation, but none of those not seeking
compensation, failed two or more of the six neuropsycho-
logic tests used to detect malingering. Heyer et al. [8]
observed patients before and after they underwent lumbar
spine surgery; 12.5% had suffered a previous stroke or
transient ischemic attack, 8.3% had undergone carotid
endarterectomy, and 42% were administered analgesic
medications after surgery. Rated pain intensity correlated
with performance on Trail-Making Part A and the Rey
Complex Figure Test (RCFT) after the surgery, but not
before; however, the relationship between pain intensity
and RCFT performance was potentially confounded by
medication use. Two other test measures did not correlate
with rated pain intensity (Controlled Oral Word Associa-
tion, Trail-Making Part B). Park et al. [9] compared patients
with fibromyalgia recruited from a university-based clinic
with healthy control subjects. Patients with other signifi-
cant health conditions or major psychiatric disorders,
 Cognitive Impairment in Patients with Chronic Pain: The Significance of Stress Hart et al.
including depression, were excluded. The patients were
impaired on measures of working memory capacity (read-
ing span and computation span), free recall of a 16-item
word list, and yes-no recognition memory of a word list
and vocabulary, and performed marginally worse on a
measure of verbal fluency. Measures of pain symptomatol-
ogy, but not of mood or fatigue, correlated with perfor-
mance on the working memory capacity and verbal
memory tests. The patients were not impaired on measures
of information processing speed (number, pattern, and let-
ter comparison); however, these tests were simple and brief
(eg, stimulus strings of three to nine segments and 30-sec-
ond trials) compared with other tests of information pro-
cessing speed that have been used to assess patients with
chronic pain (eg, Paced Auditory Serial Addition Test
[PASAT]). Furthermore, a measure of pain-related daily
dysfunction correlated with the patients performance on
these measures of information processing speed and with
performance on the tests of working memory capacity and
verbal memory. Some of these investigators [10] subse-
quently reported deficits in patients with rheumatoid
arthritis on similar letter and pattern comparison tests of
information processing speed in association with higher
levels of pain and depression.
A negative finding in a small sample of 10 control sub-
jects [11] is consistent with the type of clinical features
identified in an earlier review [5] that are most likely to be
associated with pain-relative cognitive impairment. All 10
subjects were engaged in their normal work activities and
had pain symptoms that were localized to one shoulder;
the pain did not involve multiple sites or the head, neck, or
back region. Pain was of low intensity (median visual ana-
log scale [VAS], 9%) and as short as a 3-month duration.
The Hopkins Symptom Checklist (SCL) did not indicate
any mood changes or tendencies toward somatization. The
three cognitive tests that were administered were brief (5
minutes). The pain group reported a higher level of per-
ceived stress during the tests than the control subjects did,
raising the possibility that deficits might have occurred if
the tests were more cognitively demanding.
The Role of Emotional
Factors and Chronic Stress
The effects of pain on cognitive functioning are not
related in a simple fashion to its immediate sensory-
discriminative features (ie, intensity and location) because
the concomitants of chronic pain are the more important
mediating variables [5]. Specifically, cognitive impair-
ment in patients with chronic pain has been associated
with mood changes and emotional distress and with symp-
toms and clinical features such as increased somatic preoc-
cupation, sleep disturbance, fatigue, and perceived
interference with daily activities that are potential sources
of chronic stress. A cervicoencephalic syndrome, includ-
ing dizziness, blurred vision, disturbed adaptation to light,
117
and frequent headache, tends to be associated with cogni-
tive impairment, perhaps as a result of chronic stress
because even routine activities often require concentrated
effort. The trend toward greater impairment for patients
with post-traumatic pain (without evidence of brain
injury) than for patients with other forms of pain also is
suspicious for the influence of chronic stress related to per-
ceived victimization.
Models of pain processing that distinguish the sensory,
affective, cognitive-evaluative, and behavioral dimensions
facilitate our understanding of the effects of chronic pain
on cognitive functioning. The model that has guided our
research distinguishes several stages of pain processing
[12,13,14]. The first stage, a sensory dimension, is com-
monly assessed by ratings of pain intensity. The second
stage or immediate affective response commonly is
assessed by ratings of pain unpleasantness. The third stage
relates to the meaning and implications of pain for the
patient and thus to associated emotional suffering, and is
commonly assessed by measuring pain-related emotional
states (eg, depression, anxiety, frustration) and beliefs (eg,
perceived ability to endure pain). The fourth stage refers to
illness behavior that can be assessed through ratings (eg,
lifestyle interference) or observed by the examiner or col-
lateral sources (eg, pain behaviors manifested at home or
during clinical interview).
Considerable research, including studies reviewed in
this article and previously [5], has established that emo-
tional distress frequently accompanies chronic pain.
Emotional distress is related partly to specific symptoms,
such as sleep disturbance, that are common in chronic
pain [15]. Perhaps more importantly, mood change and
chronic stress are not surprising because of the restric-
tions in daily activities, disruptions in preferred role func-
tions, losses of sources of satisfaction and reinforcement,
and changes in ones sense of identity and self-esteem
that can occur because of chronic pain [16]. Avoidant
behavior and reduced activity level can perpetuate a cyclic
disability-enhancing pattern of further avoidance in activ-
ity and associated emotional distress. For example, Chap-
man and Gavrin [17] emphasize the distinction between
pain and suffering. Suffering entails a disparity between
what people believe themselves to be and what people
are, which often occurs with poorly controlled chronic
pain. Associated psychologic stressors may include feeling
a loss of control, hopelessness, fear, and other negative
beliefs and attributions. The idea that ones pain is
uncontrollable is in itself a stressor. In addition to the
stressors of pain and associated negative thinking, sus-
tained maladaptive physiologic stress responses may
leave a person feeling sick (ie, produce or exacerbate
fatigue, dysphoria, muscle aches, sleep disturbance,
somatic hypervigilance, and mental inefficiency).
Cognitive complaints for patients with chronic pain are
more closely related to measures of emotional distress
than to sensory-discriminative aspects of pain, and are
118 Psychiatric Management of Pain
associated with motivational changes, such as a reduced
desire for activities [1820]. The following section dis-
cusses studies that relate cognitive impairment to emo-
tional distress and later stages of pain processing.
Several studies have shown that psychologic distress
and negative emotions are more closely associated with
cognitive deficits in patients with chronic pain than is pain
severity. Kewman et al. [21] found correlations between rat-
ings of pain intensity, psychologic distress (composite
measure of depression, anxiety, irritability, and energy
level), interference with daily activities, and a composite
score from a cognitive screening measure. When the effect
of distress was partialed out, pain ratings no longer corre-
lated with test performance. Grace et al. [22] found that
pain intensity and trait anxiety (but not depression) corre-
lated with measures of memory and processing speed.
When the effect of mood was partialed out, pain intensity
no longer correlated with test performance; however, after
the effect of pain intensity was partialed out, trait anxiety
still correlated with the Wechsler Memory Scale (WMS)-
Revised Delayed Recall Index. Landro et al. [23] reported
that only those patients with a history of major depression
had memory impairments, and their rated pain intensity
did not correlate with their test performance. Radanov et al.
[24] found that poor performance on a test of processing
speed was associated with lower ratings of emotional well-
being and higher levels of self-reported nervousness. In a
follow-up study [25], those patients who remained symp-
tomatic and evidenced subtle attentional impairments 6
months and 2 years later continued to rate their emotional
well-being lower. Because the latter studies did not include
ratings of pain intensity, it is unclear to what extent psy-
chologic distress predicted performance decrements inde-
pendent of pain severity.
Studies that screened patients with chronic pain for
psychiatric illnesses or otherwise that had a narrow range
of scores on measures of psychologic distress did not find
such associations, suggesting that distress or mood distur-
bance is only one factor that may contribute to cognitive
impairment. For example, Eccleston [26,27] did not find
an association between measures of distress from the
McGill Pain Questionnaire or of mood disturbance (anxi-
ety, depression) and performance on an attention-
demanding numerical interference tasks, but his patients
with pain had been screened for treatment of depressive
symptoms and severe emotional problems. In fact, his
patients and control subjects had a similar frequency of
mood disturbance [27]. Taylor et al. [28] reported subtle
impairments in processing speed and short-term memory
in two different groups of patients with chronic pain. Pain
intensity and depression levels did not correlate with test
performance, but the authors point out that there was a
narrow range of scores on both measures.
Other findings suggest that psychologic distress or suf-
fering in the form of increased somatic awareness or preoc-
cupation is associated with cognitive deficits in patients
with chronic pain. Eccleston et al. [29] found that only
those patients reporting high somatic awareness (opera-
tionalized as a greater frequency and breadth of diffuse
somatic complaints on a questionnaire) and higher pain
intensity were impaired on a version of their attention-
demanding numerical interference task. These patients
also reported higher levels of depression and anxiety; how-
ever, the relationship between the level of emotional dis-
tress and test performance was not examined. Other
studies have found associations between the level of
somatic complaints and cognitive performance in patients
with chronic pain, although clinical features that may
covary with somatic complaints were not explored system-
atically. Patients whose temporomandibular disorder
(TMD) occurred after a cervical whiplash injury (without a
loss of consciousness) reported more somatic complaints
on a modified SCL-90 and exhibited more impairment on
tests of simple and choice reaction time and memory than
patients with idiopathic TMD [30]. However, chronic pain
related to whiplash injury may be relatively more severe
and widespread [30] or associated with additional symp-
toms, such as dizziness and blurred vision [24]. Even if liti-
gation is not a confounding issue, emotional reactions and
negative attributions related to feelings of victimization
also may be important factors. Furthermore, the study by
Goldberg et al. [30] did not explore the relationship
between emotional status and cognitive function. Cote and
Moldofsky [31] found that the endorsement of somatic
items from a depression scale covaried with ratings of pain
intensity and fatigue, and with performance on a simu-
lated multitask office procedure. None of these studies
explored whether increased somatic awareness or com-
plaints uniquely contributed to cognitive impairment.
Nevertheless, these findings suggest that a somatic focus
and associated emotional reactions may increase the dis-
ruptive influence of pain on cognition by facilitating access
of pain into awareness [29].
Recent studies of patients with chronic pain implicate
emotional distress and the later stages of pain processing
in relation to cognitive impairment. Iezzi et al. [32] evalu-
ated patients with chronic pain who were recruited con-
secutively from a hospital-based pain service. Pain was
musculoskeletal in nature (eg, fibromyalgia, myofascial,
osteoarthritis), and included patients with multiple pain
sites and involvement of the neck or head. Approximately
50% of the patients were taking two or more classes of
medication, including opioids. Patients with cancer, neu-
ropathic pain, a history of major psychiatric illness or a
history of traumatic brain injury (TBI), or other neuro-
logic disorder affecting brain function were excluded. Sta-
tistical clustering procedures were used to identify groups
reporting high, moderate, and low levels of emotional
distress based on their SCL-90-R profiles. Those patients
highest in emotional distress exhibited deficits in atten-
tion and processing speed (eg, Stroop Test, PASAT), mem-
ory (WMS-R Logical Memory and Visual Reproduction),
 Cognitive Impairment in Patients with Chronic Pain: The Significance of Stress Hart et al.
nonverbal intelligence (Wechsler Adult Intelligence Scale-
Revised), and executive functions/abstraction (Wisconsin
Card Sorting Test, RCFT Copy) compared with those
patients lowest in emotional distress. The performance of
the moderately distressed group tended to be intermedi-
ate to the other two groups. Deficits were not related to
pain intensity ratings, disability/legal status, or medica-
tions. Wade and Hart [33] reported findings on the Digit
Span Test in a large sample of patients with chronic pain
(n = 736) consecutively evaluated at a pain management
clinic in a medical center. Approximately 50% of the
patients suffered from low back pain. The second and
third most frequent diagnoses were myofascial dysfunc-
tion and complex regional pain syndrome. Most patients
reported multiple pain sites. Patients with cancer-related
pain or a history of TBI or neurologic disorders affecting
cognition were excluded. The multidimensional aspects
of pain were evaluated according to the four-stage model
of pain processing. Patients completed VASs of pain sen-
sation intensity (stage 1), pain-related unpleasantness
(stage 2), and emotional states and negative illness
beliefs associated with suffering (stage 3). A structured
pain interview was used to assess illness behavior (stage
4). Step-wise multiple regression analyses were com-
pleted using measures of each pain stage as predictors
and digit span as the criterion. A final regression analysis
using only those predictor variables reliably related to
attention in the first set of analyses indicated that mea-
sures of pain-related depression, perceived lifestyle inter-
ference, and the degree of social reinforcement for pain-
related behavior were uniquely related to the deficits in
attention span. Deficits were not related to pain intensity.
Maladaptive beliefs and negative thoughts relating to per-
ceived lifestyle interference contributed to pain-related
suffering. Social reinforcement of pain behaviors (eg,
solicitous responses) may serve to further increase
somatic focus or preoccupation and, secondarily, psycho-
logic distress. A subset of these patients (n = 274) also
were administered the Verbal Paired Associate Learning
subtest of the WMS. Similar analyses revealed that deficits
in verbal learning were associated with pain-related anxi-
ety after controlling for pain sensation intensity [34].
Brown et al. [10] evaluated a large community-
dwelling sample of patients with rheumatoid arthritis (n =
121). Measures of cognition included two tests of process-
ing speed (timed letter comparison and pattern compari-
son), an inductive reasoning test that asked patients to
determine the rule that made four of five sets of letters
alike, two tests of working memory capacity (reading span
and computation span), and the free recall of two lists of
25 words. Two scales were administered that assessed pain
intensity (eg, pain at different times of the day, after physi-
cal activity) and some aspects of suffering or later stages of
pain processing (how often pain interfered with activities).
A composite measure of depression was derived from
subscales of different instruments. High levels of pain and
119
depression were associated with poor cognitive perfor-
mance in all four areas of functioning (information pro-
cessing speed, working memory capacity, reasoning ability,
and verbal memory). Structural equation modeling indi-
cated that depression mediated the relationship between
pain and cognitive functioning (ie, chronic pain causes
depression, which causes impairment in cognitive func-
tioning). The effects of pain on cognition were no longer
significant after controlling for depression. A model with
paths from pain to depression and from depression to
cognition, but not from pain to cognition, explained 55%
of the variance in general cognition.
Although the study by Park et al. [9] did not find signif-
icant correlations between measures of depression and
anxiety and cognitive performance, their findings are con-
sistent with the role of later stages of pain processing in the
cognitive impairment of patients with chronic pain. As the
authors point out, their patients with fibromyalgia were
screened carefully for depression; the mean symptom
scores were below the cutoffs for even mild depression.
Cognitive performance across multiple domains correlated
with scores on a pain subscale that primarily measured the
functional impact of pain; however, they did not correlate
with scores on a pain questionnaire that measured pain
intensity in a more focused manner [9]. The functional
impact of pain is related in large part to its meaning and
the implications for the patient (stage 3) and to resultant
behavioral changes (stage 4). Pain-related suffering associ-
ated with maladaptive beliefs and with ongoing lifestyle
disruption may not be reflected fully in a patients current
mood state.
The often observed relationship between measures of
psychologic distress or negative emotions and cognitive
performance for patients with chronic pain is perhaps not
surprising because of the literature relating depression and
anxiety to cognitive impairment. For example, two recent
meta-analytic review articles indicate global neuropsycho-
logic impairment in patients who are depressed. Veill [35]
found effect sizes ranging from a standard deviation of
0.81 to 0.97 for measures of psychomotor speed (eg, Digit
Symbol), verbal and nonverbal memory, and visuospatial/
visuoconstruction. Veill also found an effect size of 2.0 for
measures of mental speed and flexibility (eg, Trails B,
Stroop Test) [35]. Christensen et al. [36] found an average
effect size of 0.63 of a standard deviation after performing
a wide range of neuropsychologic tests. The largest effect
sizes by test category included attention and tracking
(0.98), memory mixed (1.01), and vigilance (1.20).
Effect sizes of approximately 1.0 or higher were found for
such tests as Digit Symbol, Stroop Test, Benton Visual
Retention Test, Buschke Selective Reminding Test, Animal
Naming, and the Category Test. For patients with mild
depression, the average effect size was 0.21. Prevalence
rates for depression in clinic-based chronic pain samples
range from 30% to 60% [37]. Some of the brain regions
involved in processing the affective component of the pain
120 Psychiatric Management of Pain
experience (anterior cingulate cortex [ACC]) also appear to
play a role in the cognitive induction of negative affect in
depression. The ACC is integrated with the dorsolateral
prefrontal cortex, which is implicated in executive dysfunc-
tion in depressive illness [38].
Cognitive impairment and especially memory deficits
have been found in combat-related and abuse-related post-
traumatic stress disorder (PTSD) [39], and in rape survi-
vors with PTSD who were screened for comorbid psychiat-
ric illness, substance abuse [40], and other anxiety
disorders, including obsessive-compulsive disorder, panic
disorder, and social phobia [4144]. Although memory
deficits were most common, variable impairment was
found for other abilities, including divided attention and
executive functions. Studies of healthy subjects indicate
that anxiety can negatively impact working memory and
information processing [45], learning and memory
[46,47], abstraction and problem-solving [47,48], and
response inhibition [49], suggesting that subclinical levels
of anxiety can be sufficient to interfere with functioning.
Patients with chronic pain conditions often report anxiety
levels that do not fall within the normal range; a significant
amount of the variance in reported pain may be explained
by anxiety [5052]. In a recent study [53], patients with
high anxiety reported greater affective responses to cold
pressor pain and higher levels of sensory pain, suggesting
that anxiety may predispose otherwise healthy people to
have negative responses to painful events. Ploghaus et al.
[54] compared activation responses with thermal stimuli
using functional magnetic resonance imaging (fMRI) while
varying visual signals to moderate anxiety level. One visual
signal (low-anxiety condition) was followed consistently
by thermal stimulation of moderate intensity. A second
visual signal (high-anxiety condition) was followed by the
same noxious stimulation on most trials, but occasionally
by a much stronger thermal stimulus. The entorhinal cor-
tex of the hippocampal formation (an area important for
memory) responded differentially to the same thermal
stimuli, depending on whether anxiety was induced; the
activation pattern predicted activity in other brain regions
associated with affective pain processing (perigenual cin-
gulate) and intensity coding (mid-insula). The entorhinal
cortex may be part of the neural network that mediates the
impact of pain-related emotional distress on cognitive
functions such as memory.
Neuroanatomic Correlates
and the Role of Stress Responses
Anterior cingulate cortex
Neuroimaging studies involving patients with clinical pain
consistently have shown changes at the ACC, including
areas associated with the emotional response to pain
[2,55]. The ACC is an area of the brain involved in the
integration of affective-motivational dimensions of
experience and various cognitive processes [56,57]. The
affective subdivision of the ACC has connections to struc-
tures such as the amygdala, anterior insula, and orbitofron-
tal cortex and has been implicated in the modulation of
affective states and emotional responses and in the evalua-
tion of the emotional valence and motivational salience of
information. For example, emotional responses (eg, fear
and pleasure) may follow electrical stimulation in healthy
subjects. Cingulectomy and cingulumotomy have been
used to treat patients with pathologic aggression,
obsessive-compulsive behaviors, and depression. Activa-
tion of this region has been associated with emotional pro-
cessing (eg, recognition of affect in facial expressions,
responding to emotionally valenced words) and symptom
provocation in patients with psychiatric disorders. In con-
trast, the cognitive subdivision of the ACC has connections
to structures such as the lateral prefrontal cortex, parietal
cortex, and premotor areas and has been implicated in the
executive control of attention, effortful information pro-
cessing, and response selection, particularly under condi-
tions that involve novelty, divided attention, conflicting
information, working memory, or error detection. This
area also is implicated in motor intention/control. Fernan-
dez-Duque and Posner [58] emphasize the role of the ACC
in executive attention that involves task switching, inhib-
itory control, error detection, processing novel stimuli, exe-
cuting novel actions, and allocating attentional resources.
Not surprisingly, activity is increased at the ACC in antici-
pation of a cognitively demanding task.
In regards to attentional control and pain processing,
the ACC is part of a cortico-thalamo-mesencephalic net-
work mediating selective attention to painful stimuli, but
also is involved in attentional shifting [59]. The latter
investigators found that painful stimulation during an
auditory discrimination task intended to divert attention
from pain produced a regional cerebral blood flow (rCBF)
increase only in the mid-part of the ACC. The areas of the
ACC involved in orienting responses to painful stimuli and
those activated in response to increasing pain unpleasant-
ness appear to be adjacent [60].
The integration of emotional and cognitive self-
regulation at the ACC appears to include the executive con-
trol of attentional resources under conditions producing
emotional distress [56,58,61]. For example, the ACC is acti-
vated after error detection or negative feedback, and is the
likely source of an event-related potential called error-
related negativity. This error-related activity partly reflects
the level of motivation for error detection (and thus the
allocation of attentional resources) and also is correlated
with negative affect (and thus the amount of distress asso-
ciated with making an error). The amount of the stress
associated with making an error seems to depend on the
personality dimension of negative emotionality, which
corresponds to the construct of trait neuroticism.
As an area of the brain that modulates emotional reac-
tivity and contributes to the executive attentional system, it
is not surprising that the ACC plays a role in pain process-
 Cognitive Impairment in Patients with Chronic Pain: The Significance of Stress Hart et al.
ing and appears to be an integral component of neural sys-
tems mediating the impact of pain-related stress on
cognitive functioning. Specifically, the ACC may mediate
the affective-motivational and cognitive-evaluative compo-
nents of the pain experience related to suffering and the
allocation of attentional resources under conditions of
pain-related emotional distress. The activation of the ACC
appears to reflect the degree of pain-related distress experi-
enced [62]. The latter investigator had subjects immerse
their hand in water under hypnotic suggestions for
increased or decreased pain-related unpleasantness.
Positron-emission tomography (PET) scans revealed
greater activation during the condition of increased
unpleasantness compared with the condition of decreased
unpleasantness only in the ACC. Patients with chronic
pain treated successfully with cingulumotomy may con-
tinue to experience painful sensations, but not the associ-
ated emotional suffering; anxious patients tend to be more
likely to benefit from the surgery [63].
It has been speculated that, because of the extent to
which the ACC is involved in pain processing and atten-
tional mechanisms, the competitive demand may interfere
with cognitive functioning [34]. Because painful stimulation
and related emotional distress are attention-demanding, the
reserved capacity of the ACC to allocate attentional
resources may be limited. The plausibility that competitive
demand on finite attentional resources may be expressed at
the ACC is supported by neuroimaging studies. PET scan
findings suggest that the interference effects in performing
two attention-demanding tasks simultaneously can occur
centrally at the ACC or prefrontal regions [64]. The areas of
the ACC that are activated by painful stimuli partially over-
lap those activated during orienting responses and target
detection [2]. Another study found substantial ACC
regional activation overlap on PET scans when patients per-
formed a task that required sustained and divided attention
during noxious heat stimulation [65].
The meta-analytic study of Bush et al. [56] indicates
that the cognitive subdivision of the ACC is activated by
various attention and cognitive-demanding tasks, and
deactivated (ie, reduced blood flow or fMRI signal) by tasks
that relate to emotional content; the affective subdivision
shows the opposite pattern of activation and deactivation.
The suppression of the cognitive subdivision during tasks
with emotional content (and vice versa) may be a mecha-
nism involving the ACC by which emotional distress dis-
rupts attentional control and cognitive efficiency. In
particular, cognitive subdivision activity may be sup-
pressed during pain-related distress or the processing of
the affective-evaluative components of the pain experience
(ie, suffering). Depressive illness, experimentally induced
emotional states in healthy subjects, and the anticipation
of pain have all been associated with the deactivation of
the cognitive subdivision of the ACC [56]. Because of the
identified role of the cognitive subdivision of the ACC,
effortful information processing likely is to be disrupted
121
with pain-related distress, whether by mechanisms related
to competitive demand on finite attentional resources or
reciprocal suppression. These information processing
demands include those related to the proposed role of the
ACC in responding to pain (eg, selecting and organizing
motor responses and mediating the learning associated
with prediction and avoidance of noxious stimuli) [57]. In
addition to its role in information processing, there is
some evidence that the ACC contributes to a memory sys-
tem [66,67]. Memory processes may be potentially dis-
rupted with pain-related distress by the same mechanisms
of competitive demand, interference, or reciprocal suppres-
sion at the ACC.
Stress-mediated mechanisms
The effects of chronic stress on cognition and the mecha-
nisms by which stress results in changes in brain structure
and function have important implications for cognitive
functioning in patients with chronic pain. Manifestations
of chronic stress, including excessive sympathetic nervous
system activity, neuroendocrine response, and possibly
immune system activity, may be part of a maladaptive
response in patients with chronic pain [17]. Dysregulation
of the hypothalamic-pituitary-adrenocortical (HPA) axis
has been associated with mood disorders and PTSD, pre-
sumably reflecting the effects of chronic stress or maladap-
tive stress responses for patients with these disorders.
Furthermore, patients with mood disorders and PTSD have
reductions in brain volume, particularly in the region of
the hippocampus [39,68,69]. For patients with a history of
recurrent major depression, hippocampal volume showed
an inverse correlation with the total days the patients were
depressed [69]. The idea that chronic stress may produce
reductions in brain volume is supported by recent findings
in healthy control subjects [70]. Trait neuroticism, which
reflects the general tendency to experience negative emo-
tions or stress reactivity (as characterized by these inves-
tigators), showed a negative association with the ratio of
the brain to the remainder of intracranial volume. Specifi-
cally, the tendency to experience anxiety and negative emo-
tions (eg, shame or embarrassment) in social situations
was related to reductions in brain volume. The authors
note that trait neuroticism has been associated with hyper-
cortisolemia and with an increased future incidence of
affective and anxiety disorders. It has been reported that
20% of patients with chronic pain from a multidisciplinary
pain program met predefined criteria for one of four
McGill-Melzack Pain Index pain subgroup classifications
(emotionally overwhelmed) and had elevated scores on
the same measure of trait neuroticism [71].
A considerable amount of evidence exists that impli-
cates chronobiologic dysregulation of the HPA axis in
patients with chronic pain. Elevated cortisol levels and
reduced melatonin concentrations in patients with cluster
and migraine headaches [72,73] have been interpreted as a
disorder of hypothalamic circadian function [74]. In a
122 Psychiatric Management of Pain
study of patients with TMD pain, Korszum et al. [75] found
markedly increased daytime cortisol levels and a 1-hour
phase delay in the timing of maximum cortisol levels rela-
tive to control subjects. Findings in patients with fibromy-
algia include normal to increased plasma adenal
glucocorticoid secretion in the morning and evening, but
low 24-hour urine-free cortisol levels and an exaggerated
pituitary response to challenge testing [76]. Extended stud-
ies at 10-minute intervals over a 24-hour period found sig-
nificant differences in the pattern of circadian secretion of
adrenocorticotropic hormone and cortisol, with a general
hypoactivation. Crofford [77] has reviewed evidence of
HPA axis involvement in acute and chronic pain, including
the fibromyalgia spectrum of somatic pain and rheumatic
diseases. Ehlert et al. [78] noted that, in contrast to HPA
axis hyperactivity in depression, the findings for PTSD,
chronic fatigue, and stress-related bodily disorders, such as
idiopathic pain syndromes, frequently suggest diminished
HPA activity. Thus, findings of HPA dysregulation in
chronic pain include hyperactivity and hypoactivity. This is
consistent with a chronobiologic disturbance characterized
by aberrant HPA activity and cortisol levels that are vari-
ably higher and lower in patients with chronic pain than in
control subjects over the course of a day, and complex
interactions with other neuroendocrine functions, espe-
cially those relating to melatonin, serotonin, and endoge-
nous opioids [79].
Additional evidence of dysregulation of the HPA axis
in pain syndromes comes from studies examining treat-
ment effects for acute and chronic pain. Specifically, pain
relief is associated with reduced cortisol levels and HPA
activity. For example, local anesthesia can reduce immu-
nologic and hormonal responses (ie, increases in plasma
epinephrine and serum cortisol) to acute painful stimula-
tion [80], and septal stimulation-inducing analgesia can
produce a decrease in plasma cortisol and in gastric ulcer-
ation [81]. Preoperative acupuncture can reduce postop-
erative pain and nausea and plasma cortisol and
sympathoadrenal system activity in patients who have
undergone surgery [82]. Sugano and Nomura [83] found
that water exercise and stretching programs produced
lower salivary cortisol, subjective pain, and anxiety scores
in patients with chronic low back pain. Bellometti and
Galzigna [84] found that a combination of mud pack and
antidepressant treatment positively rebalanced the stress
response system, reduced pain symptoms, and improved
the quality of life in patients with fibromyalgia. Pizzofer-
rato et al. [85] found that a single thermal mud treatment
significantly decreased plasma cortisol and pain com-
plaints for patients with osteoarthritis. Microcurrent cra-
nial and body area stimulation studies have shown
elevated plasma serotonin, -endorphin, -aminobutyric
acid, and dehydroepiandrosterone, along with dimin-
ished levels of cortisol and tryptophan and concomitant
improvements in symptoms of pain, insomnia, and
depression [86].
The hypothesis that maladaptive stress responses may
be a cause of cognitive impairment in patients with
chronic pain is plausible because of the evidence for a link
between stress-related dysregulation of the HPA axis and
neuronal plasticity. McEwen [87] reviewed animal and
human research that supports a link between stress and
neuronal plasticity at the hippocampus. Repeated stress
suppresses neurogenesis of dendate gyrus neurons and
produces atrophy of dendrites in the CA3 region. Den-
dritic atrophy appears to be the result of excitatory amino
acid (glutamate) release during repeated stress, which is
facilitated by circulating adrenal steroids. Chronic adrenal
steroid (eg, glucocorticoid) exposure increases N-methyl-
D-aspartate (NMDA) receptor binding. Serotonin released
in response to stress also may facilitate excitatory amino
acid activity at the NMDA receptor. Glutamate is a key
neurotransmitter that mediates central nervous system
hypersensitivity, including sensitization associated with
chronic pain [8890]. Glutamate increases intracellular
levels of calcium ions (Ca2+), which has been linked to
excitotoxic effects. Sheline et al. [69] suggest that, in addi-
tion to glucocorticoid-induced neurotoxicity, other poten-
tial mechanisms include corticotrophin-releasing factor
neurotoxicity and the loss of neuroprotective brain-
derived neurotrophic factor.
Traumatic stress and elevated adrenal steroids are asso-
ciated with signs of atrophy in the human brain [87], but
reductions in brain volume in psychiatric disorders such as
PTSD and recurrent major depression suggest that the
human hippocampus is particularly sensitive. Prolonged
glucocorticoid exposure reduces hippocampal cell number
[91]. Chronically elevated levels of glucocorticoids in
healthy elderly subjects may be associated with hippocam-
pal atrophy [92]. The hippocampus is a primary target for
adrenal steroids. Increased glutamate production and
release in response to HPA activation has been implicated
in reduced hippocampal volume in patients suffering from
anxiety and depressive disorders [93,94]. A metabotropic
glutamate receptor antagonist (2-methyl-6-phenylethynyl-
pyridine) has been shown to possess antidepressant and
anxiolytic properties [95]. In patients who are depressed,
volume loss in the hippocampus correlates with volume
loss in the core nuclei of the amygdala where glutamatergic
pyramidal cells predominate [69]. The latter author sug-
gests that over-excitation in one structure can produce
damage in the other through reciprocal connections
between the hippocampus and amygdala.
Animal models of stress-induced atrophy suggest that
periodic HPA axis activity is sufficient to cause damage
[87]. McEwen [87] postulates that repeated HPA and asso-
ciated autonomic and neurochemical reactivity to experi-
ences in the course of PTSD and recurrent depressive
illness may underlie progressive neuronal structural
changes and eventually cell loss. This same explanation
would seem consistent with evidence of reduced brain vol-
ume in patients high in trait neuroticism who tend to
 Cognitive Impairment in Patients with Chronic Pain: The Significance of Stress Hart et al.
experience more life events as stressful and are more sus-
ceptible to psychologic distress.
Regional brain volume loss hypothesized to be a conse-
quence of repeated stress and elevated cortisol levels have
been associated with cognitive impairment in human sub-
jects. For example, Bremner [39] reported that deficits in
memory correlated with decreases in hippocampal volume
in one of their PTSD patient samples; Sheline et al. [69]
found impaired verbal memory and smaller hippocampal
volumes in patients with a history of recurrent major
depression who were in remission. Administration of the
endogenous glucocorticoid cortisol can impair memory
function in healthy subjects [96,97]. Newcomer et al. [97]
did not find effects for tests of sustained or selective atten-
tion, but Kirschbaum et al. [96] found effects for tests that
required spatial thinking and memory (judgements about
spatial location after mental rotation or reversal of direc-
tion). Memory deficits occur in association with stress-
induced (eg, public speaking, mental arithmetic) cortisol
elevations in healthy subjects [96,98]. Lupien et al. [98]
identified approximately one third of their group as corti-
sol responders; sampling over time showed that cortisol
levels increased early-on, suggesting that anticipation of
stress played a significant role in the observed memory def-
icits in this subgroup. Twelve-hour urinary-free cortisol
excretion has been negatively associated with memory per-
formance in healthy older women, but not men [99]. Lon-
gitudinal studies of healthy older adults have shown that
increases in cortisol levels over a period of years is associ-
ated with cognitive impairment and decline in memory
[99,100]. Lupien et al. [100] found that the slope of the
change in plasma cortisol levels over a period of up to 4
years was correlated negatively with cognitive functioning.
The patients who showed an increase in cortisol levels and
had a high basal level in the final year were impaired on
measures of verbal paired-associate learning and selective
attention (visual search task), but not on measures of
memory from the WMS or on tests of divided attention or
naming. A 1-year follow-up study also demonstrated an
impairment in vigilance in those patients with increasing
cortisol levels who did not develop the same degree of
hypersecretion [101]. Furthermore, prolonged cortisol ele-
vations predicted hippocampal atrophy [92]. Seeman et al.
[99] similarly found that increases in the level of urinary
cortisol excretion over a period of almost 2.5 years was
associated with actual declines in memory performance in
women (but not men), although there were no effects on
measures of abstraction and visuoconstruction. In a recent
study, Lupien et al. [102] demonstrated some of the com-
plexity in relating cortisol levels with cognitive impair-
ment. Pharmacologic manipulation of glucocorticoids had
different effects on memory function depending on a
patients cortisol history. Inhibition of cortisol secretion
with administration of metyrapone impaired memory in
123
those patients with a history of moderate cortisol levels;
the deficit was reversed after hydrocortisone replacement.
In contrast, metyrapone did not effect memory in those
with a history of high cortisol levels and current memory
deficits, but hydrocortisone treatment significantly
decreased delayed memory. Memory problems associated
with repeated stress and HPA axis dysregulation may be
specifically mediated by glutamates neurotoxic effect on
the hippocampus. For example, Alvarez and Banzan [103]
have shown that chemical stimulation of ventral hippoc-
ampus glutamate receptors inhibit learning and memory
in adult rats. A metabotropic glutamate receptor antagonist
can reverse the learning deficit.
The finding of Lupien et al. [98] that memory impair-
ment was associated with early cortisol elevations corre-
sponding to the anticipation of stress is particularly
important for understanding the role of stress in the cogni-
tive functioning of patients with chronic pain. The belief
that pain symptoms are inevitable is a core feature of the
chronic pain syndrome for many patients. The anticipation
of pain is a significant psychologic stressor that may be
associated with dysregulation of the HPA axis. Further-
more, the anticipation of pain has been associated with
modified activity at ACC regions that play a role in effort-
ful information processing [56] and at ACC regions that
have been implicated in anxiety and stress reactions [2].
Therefore, the anticipation of pain may disrupt informa-
tion processing and the allocation of attentional resources
through neuronal activity at the ACC. A recent study
showed that anticipation of an impending and unpredict-
able pain stimulus increased rCBF in the caudal portion of
the ACC and anticipation of an inevitable, but predictable
pain stimulus resulted in a decrease of rCBF [104]. Subjects
in this study reported promptly attending to or intention-
ally distracting their attention from pain. To the extent that
aspects of chronic clinical pain are difficult to predict, this
observation raises the possibility that a patient may
become increasingly vigilant, emotionally aroused, and
somatically focused, which could have the effect of reduc-
ing the capacity for effortful cognitive processing.
The negative effect of HPA axis dysregulation on cogni-
tive function is consistent with the idea that the concomi-
tants of chronic pain (eg, emotional distress) are related to
neuropsychologic deficits. It is plausible that the patterns
of HPA axis dysregulation in chronic pain represent vari-
ants of the periodic HPA and the autonomic and neuro-
chemical reactivity that McEwen [87] postulates may
underlie progressive neuronal changes. There is evidence
from longitudinal studies [99] that a decline in cortisol lev-
els may be associated with an improvement in cognition.
Effective treatment of chronic pain symptoms may mini-
mize repeated HPA axis activation, reduce cognitive ineffi-
ciency as a result of associated distress, and partially reverse
any stress-related changes in brain structure or function.
124 Psychiatric Management of Pain
Conclusions
The studies that have been reviewed suggest an association
between psychologic distress and cognitive impairment in
patients with chronic pain. In particular, pain-related neg-
ative emotions and variables that mediate suffering (eg,
interference with activities and increased somatic vigi-
lance) have been identified in a number of studies as cor-
relates of cognitive impairment. Studies employing
multiple regression analysis or structural equation model-
ing have extended earlier findings that suggested that psy-
chologic distress is related to cognitive impairment
independent of the effects of pain intensity. However,
beyond this general distinction between sensory-
discriminative and later stages of pain processing, research
has not systematically and comprehensively explored the
interrelationships among the numerous variables that
potentially mediate the association between psychologic
distress and cognitive impairment.
The ACC appears to be play an important role in pain
processing, especially with regards to the affective-
motivational dimension of the experience. As an area of
the brain that modulates emotional reactivity and contrib-
utes to an executive attentional system, it may be an inte-
gral component of the neural system that mediates the
impact of pain-related emotional distress on cognitive
functioning, including the allocation of attentional
resources. Mechanisms related to competitive demand on
resources, interference effects, or reciprocal suppression
between the affective and cognitive subdivisions of the
ACC may underlie the disruption of cognitive function.
Maladaptive physiologic stress responses and dysregula-
tion of the HPA axis is another plausible cause of cognitive
impairment in patients with chronic pain, including mem-
ory deficits secondary to effects on hippocampal function.
Physiologic responses to repeated stress have been related
putatively to changes in brain structure and function. A
particularly intriguing possibility is that the anticipation of
pain symptoms that are difficult to predict, especially in
those patients who are high in trait neuroticism, is a signif-
icant stressor that repeatedly activates the HPA axis and
ACC areas, resulting in cognitive impairment.
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